[unreadable] This program uses very-high-frequency ultrasound (VHFU) transducers (center frequencies near 50 MHz) to sense fine-scale physical changes that are induced in tissue by lower frequency transducers (3-10 MHz) used in diagnostic and therapeutic ultrasound (TU). It develops and tests dual coaxial transducers integrated with a versatile digital system. Four operational modes non-invasively characterize microstructure properties with 0.05 mm resolution. First, the system evaluates elastic properties of tissue microstructure by tracking submicron displacements remotely induced by low-frequency beams. Second, it quantifies cell-level changes induced during TU, using VHFU spectra to quantify micron changes indicative of apoptosis and necrosis. Third, it senses very high order harmonics due to non-linear propagation in diagnostic and TU beams; this mode also detects small gas bubbles that affect TU. Fourth, the system characterizes size variations in ultrasonic contrast agents as they dynamically respond to typical diagnostic frequencies; this will aid investigations of improved agents, including those for drug delivery, and enable high resolution tracking of blood vessel with diameters near 0.1 mm. Together, these novel capabilities will significantly impact basic laboratory and animal biophysical investigations of: microstructural elasticity, as well as changes due to TU; the dynamics of cellular effects during TU; non-linear beam propagation and bubble production (during TU); and, the fine-scale dynamic responses of contrast agents to conventional transducers. These capabilities will also enable basic studies benefitting diagnostic applications of radiation-force elastography (for remote, noncontacting palpation), chronic tissue responses to therapeutic agents, harmonic imaging, and very-high resolution imaging of contrast agents stimulated by conventional transducers. They will also provide novel, highly significant clinical applications where VHFU examinations are applicable; these include examinations of the eye, skin, superficial vessels, and tissues accessed during intraoperative procedures. [unreadable] [unreadable]